Glial cells play a key role in neuronal development and function. However, the signals exchanged by glial cells and neurons are poorly understood. Increasing evidence supports the notion that ephrins and Eph receptors play an important role in the interactions between glial cells and neuronal axons as well as dendrites in different parts of the central and peripheral nervous system. We recently discovered a new form of neuron-glia communication that involves the ephrin-A3 ligand expressed on the surface of astrocytes in the hippocampus and the EphA4 receptor tyrosine kinase expressed on dendritic spines. Dendritic spines are small protrusions on neuronal dendrites that make synaptic contact with axonal terminals. Typically, mature spines have an enlarged head connected to the dendrite through a narrow neck. Changes in the shape, size and number of dendritic spines in the hippocampus likely contribute to learning and storing longterm memories. Our evidence suggests that the interplay between ephrin-A3 and EphA4 mediates a form of repulsive communication between astrocytes and neurons that counteracts signals promoting the enlargement of spines and prevents distortion and disorganization of the spines. This may represent a mechanism regulating spine remodeling during learning and memory formation. Importantly the communication likely is bidirectional, with ephrin-A3 also initiating signals that affect the properties of astrocytes coming in contact with EphA4-positive dendrites. The goal of this project is to evaluate the role of glial ephrin-A3 in the regulation of dendritic spine development and remodeling and synaptic transmission in hippocampal neurons. Furthermore, we will investigate the signaling pathways mediated by ephrin-A3 and their role in astrocyte physiology. Recently obtained ephrin-A3 knockout mice will be important tools to achieve these goals. The proposed research will provide information on whether mutations in the ephrin-A3 gene contribute to neurological diseases characterized by abnormalities in dendritic spines[unreadable]including mental retardation, autism, epilepsy, and schizophrenia[unreadable]and whether the ephrin-A3 knockout mouse may represent a useful neurological disease model. Strategies to manipulate ephrin function in glial cells could help treatment of neurological disorders involving aberrant neuron-glia interactions in the hippocampus and other regions of the nervous system.